The interleukin-17 (IL-17) family consists of a subset of cytokines that participate in both acute and chronic inflammatory responses. Since the discovery of IL-17A (also called IL-17 or CTLA8) in 1993, five other members of this family IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F have been identified based on amino acid sequence homology. Notably, IL-17A is a pro-inflammatory cytokine produced by Th17 cells, a CD4+ T helper cell subset that has been shown to regulate tissue inflammatory responses. Recent studies indicate that IL-17A can also be produced by other cell types during inflammatory responses including CD8+ T cells, and γδ T cells, and innate lymphoid cells. Tremendous effort has been devoted to understand the function of IL-17A, demonstrating that that this pro-inflammatory cytokine plays a critical role in the pathogenesis of autoimmune diseases, metabolic disorders and cancer.
IL-17A signals through IL-17 receptor complex (IL-17RA and IL-17RC subunits) to transmit signals into cells. Wright, et al., Journal of immunology 181, 2799-2805 (2008). While the IL-17R adaptor protein Act1 interacts with TRAF6 and TRAF2/5 to induce transcriptional and post-transcriptional control of inflammatory gene expression, respectively, TRAF4 binds Act1 to promote ERK5 activation for cell proliferation. Bulek et al., Nat Immunol 12, 844-852, (2011). The main function of IL-17A is to coordinate local tissue inflammation via the upregulation of proinflammatory and neutrophil-mobilizing cytokines and chemokines (including IL-6, G-CSF, TNF-α, IL-1, CXCL1 (KC), CCL2 (MCP-1), CXCL2 (MIP-2)), as well as matrix metalloproteases to allow activated T cells to penetrate extracellular matrix. IL-17A has also been implicated in smooth muscle function and airway remodeling. Previous studies have suggested a central role for IL-17A in severe asthma and COPD (Al-Ramli et al., J Allergy Clin Immunol 123, 1185-1187 (2009)), those patients are typically unresponsive, or poorly responsive to currently available drugs. Indeed, high levels of IL-17A are found in induced sputum, bronchial biopsies and serum obtained from patients with severe asthma. Wang et al., Current allergy and asthma reports 11, 388-394 (2011). In addition, IL-17A levels were also increased in synovial fluids from arthritis patients, serum and brain tissue of multiple sclerosis patients, skin lesions of psoriasis patients, serum and tumor tissues of cancer patients. Gu et al., Cytokine 64, 477-485 (2013). Importantly, deficiency of IL-17A signaling components attenuated the pathogenesis of several autoimmune inflammatory diseases (such as allergen- and non-allergen-induced asthma, psoriasis, rheumatoid arthritis, multiple sclerosis) and tumorigenesis in animal models. Silverpil, E. & Linden, A., Expert review of respiratory medicine 6, 173-186, (2012). Thus, IL-17A pathway is a promising drug target for treatment of a wide spectrum of autoimmune inflammatory disorders and cancer.
Targeting IL-17A binding to IL-17RA has been reported to be an effective strategy for treating IL-17A-mediated autoimmune inflammatory diseases. Miossec, P. & Kolls, J. K., Nat Rev Drug Discov 11, 763-776 (2012). Monoclonal neutralizing antibodies against IL-17A has been developed as drug candidates for IL-17A inhibition. Brown et al., The Journal of dermatological treatment 26, 32-36 (2015). Preclinical studies have yielded promising results in murine models of allergic lung diseases. Lajoie et al., Nature immunology 11, 928-935 (2010). Clinical trials with these antibodies have shown promising results with IL-17A-mediated inflammatory diseases, including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis. Robinson et al., Current allergy and asthma reports 13, 587-595 (2013). Anti-IL17A antibody (Cosentyx/secukinumab from Novartis) was approved by FDA (January 2015) for the treatment of psoriasis and is currently on 50 clinical trials for various autoimmune diseases including asthma. Extreme efficacy (greater than 85% responding rate) was observed for psoriasis. Other anti-IL-17 antibodies (Ixekizumab from Eli Lily and MSB0010841 from Merck) are also in active clinical trials. However, given the considerable cost for antibody production and limitation for administration (only through intravenous route), it is advantageous to develop cost-effective alternatives such as small molecule drugs for IL-17A inhibition.